Research/Scholarly Activity

Understanding the interplay between hosts and pathogens is vitally important for rational design of treatment for microbial infections and diseases. I am particularly interested in host-pathogen interactions, immunology, microbial pathogenesis, the problem of evolution of virulence and identifying factors that are associated with virulence, from both the host and microbial perspectives. To study evolution-related & host-pathogen interaction questions, I utilize the pathogenic & medica...

Understanding the interplay between hosts and pathogens is vitally important for rational design of treatment for microbial infections and diseases. I am particularly interested in host-pathogen interactions, immunology, microbial pathogenesis, the problem of evolution of virulence and identifying factors that are associated with virulence, from both the host and microbial perspectives. To study evolution-related & host-pathogen interaction questions, I utilize the pathogenic & medically relevant fungus Cryptococcus neoformans. C. neoformans infects a wide variety of hosts and causes cryptococcosis, a common opportunistic infection in AIDS patients which results in fungal meningitis.

Current Research Projects

1. Determine whether gender-associated differences in susceptibility to C. neoformans are due to hormonal effects on the host immune response and/or hormonal effects on the pathogen

One of the more interesting aspects of C. neoformans interactions with the host is the large discrepancy in the incidence of infections in male and female patients, with males having a higher incidence of C. neoformans infection and disease than females. This gender-related difference has been observed in dozens of studies and suggests underlying differences in the interactions of the immune response to C. neoformans infection and differential expression of microbial factors between males and females. We have found differences in the immune response of ex vivo male or female macrophages to C. neoformans, PLoS One, 2013. Currently, we are characterizing gender-specific and microbial factors in clinical isolates to determine which factors are involved in the gender susceptibility difference to C. neoformans.

Another key aspect of the C. neoformans host-pathogen interaction is with host macrophages. I am collaborating with Dr. Dave Nelson (MTSU) to understand how C. neoformans modulates cell signaling, and the downstream consequences on the immune response, in macrophages. We published some of this work in August 2016 in JBC where we showed that intracellular C. neoformans specifically modulates NF-κB translocation into the nucleus. We found that, in contrast to the slight attenuation of NF-κB translocation to the nucleus caused by purified GXM, intracellular C. neoformans delayed and attenuated translocation of NF-κB into the nucleus in RAW264.7 macrophages in a burden-dependent manner. Importantly, this resulted in no downstream expression of TNF-α, a major pro-inflammatory cytokine, suggesting a new mechanism by which C. neoformans suppresses the host immune response.

This project has been extended to look at differences in cell signaling when macrophages are activated by lipopolysaccharide versus interferon-γ and then infected with C. neoformans. We have RNAseq data suggesting that C. neoformans is differentially altering macrophage cell signaling once it has been engulfed by the macrophage. We are currently validating some of the identified genes using Western blot analysis.

One of the major concerns with a C. neoformans interaction with the host is how best to treat the infection. A key problem is that the current antifungal drugs used to treat a C. neoformans infection have high toxicity, which is tricky because patients are often treated long-term. Another problem is that many strains are rapidly developing drug resistance. Thus, new therapeutics are desperately needed. I have a number of collaborations studying how various compounds inhibit growth of C. neoformans and C. gattii (infects immune competent hosts), a few of which were recently published (Frontiers in Microbiology, 2017 and ACS Medicinal Chemistry Letters, 2016).

4. Determine genes involved in C. neoformans virulence.

The ability of C. neoformans to infect a broad range of hosts, including immune competent individuals, makes the study of its virulence mechanisms & host-pathogen interactions crucial for much needed therapies. I have microarray data comparing both mouse-passaged and galleria-passaged C. neoformans strains that identified genes that may be involved in virulence. Thus, the characterization of these genes and their role in virulence are perfect projects to train students in molecular biology and microbiology, ensuring student success and a new generation of future scientists.

Thus, most of the projects in the laboratory center around host-pathogen interactions, microbial pathogenesis, the evolution of virulence, and the immune response to C. neoformans infection.

I am always interested in talking to prospective graduate and undergraduate students about working in the lab.

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